MECHANISMS OF MOUSE HEPATITIS VIRUS HOST RANGE EXPANSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 模型小鼠肝炎病毒(MHV)依赖于其刺突蛋白与靶细胞结合。一旦结合，Spike引导随后的病毒-细胞膜融合，从而导致进入并通过延伸调节宿主范围。Spike蛋白表现出I类融合蛋白的特征，类似于流感的融合蛋白。以前对MHV和其他I类病毒的研究已经证明，保守的七肽重复区域(对融合过程至关重要的区域)及其附近的突变可以导致宿主范围的改变。假说是，Spike蛋白在融合机制中有一个固有的“松弛”，可能在某些选择性环境下暴露，导致宿主范围改变。这个项目有两个目标。第一个是检测以前分离的MHV宿主范围突变株的Spike蛋白的生化特性。第二项研究将研究当使用一种融合抑制肽(类似于药物Fuzeon)对七肽重复序列施加选择性压力时，如果有任何突变会导致什么结果。通过将这些研究结合起来，应该可以更清楚地了解MHV如何跨越物种障碍，并可能扩展到其他I类病毒。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The model coronavirus Mouse Hepatitis Virus (MHV) is dependent upon its Spike protein for target cell binding. Once bound, Spike directs subsequent virus-cell membrane fusion thus leading to entry and by extension regulating host range. Spike protein displays the features of a Class I fusion protein, similar to the fusion proteins of Influenza. Prior research with MHV and other Class I viruses has demonstrated that mutations in and adjacent to conserved heptad repeat regions (regions vital to the fusion process) can lead to altered host range. The hypothesis is that the Spike protein has an inherent "slack" in the fusion mechanism that may be exposed under certain selective environments leading to altered host range. This project has two goals. The first is to examine the biochemical properties of Spike proteins from previously isolated MHV host range mutants. The second will examine what, if any, mutations result when selective pressure is applied to the heptad repeats using a fusion inhibiting peptide, similar to the drug Fuzeon. By combining these studies, a clearer picture of how MHV can cross the species barrier should be developed and possibly extended to other Class I viruses.